Characterisation of a mouse model of chronic cerebral hypoperfusion and its application to investigating the impact of hypoperfusion on the development of Alzheimer’s disease

Download

Date

Author

Metadata

Abstract

The integrity of brain white matter is vital for the interneuronal signalling
between distinct brain regions required for normal cognitive function. White matter
integrity is compromised with ageing and could contribute to age-related cognitive
decline. Chronic cerebral hypoperfusion is thought to underlie the development of
white matter pathology and cognitive changes, often seen in the elderly.
Additionally, the development of regional hypoperfusion and white matter damage
are thought to be early events in Alzheimer’s disease (AD) pathogenesis. This thesis
set out to test the hypothesis that chronic cerebral hypoperfusion underlies the
development of white matter pathology and cognitive decline and also that chronic
cerebral hypoperfusion causes the development of Ab pathology in AD.
The first aim was to investigate the impact of hypoperfusion on the
development of white matter damage and different aspects of cognition in a mouse
model of chronic cerebral hypoperfusion. Two studies were undertaken to address
this. The first study examined the temporal development of pathology following
hypoperfusion induced by bilateral carotid artery stenosis (BCAS) using microcoils
Hypoperfusion was induced in wild type (WT) mice and the pathological changes
examined at one week, two weeks, one month and two months. Hypoperfused
animals developed a diffuse and widespread white matter pathology, present from
one week, which occurred predominantly in the myelin component of white matter;
this was accompanied by minimal axonal damage. A second study examined the
impact of hypoperfusion on different aspects of spatial memory and further
investigated pathological changes in the model at one and two months. Behavioural
testing revealed a significant impairment in spatial working memory but not episodic memory or spatial reference memory in hypoperfused animals. In the same mice,
pathological assessment indicated that there was a significant increase in levels of
myelin damage and elevated levels of microglial activation as compared to shams.
These results demonstrate that modest reductions in cerebral blood flow are
sufficient to cause the development of white matter damage and the development of
cognitive deficits.
The second aim was to investigate the impact of hypoperfusion on the
development of white matter and amyloid pathology in a mouse model (3xTg-AD) of
AD. To address this, using 2 different sizes of microcoils (0.18mm and 0.16mm
internal diameter) BCAS of varying severities was induced in 3xTg-AD mice and
white matter and Ab pathology were assessed at one month. Circle of Willis (CoW)
architecture was also compared between WT and 3xTg-AD mice. Overall white
matter pathology was not exacerbated in experimental 3xTg-AD mice with BCAS
induced by 0.18mm coils. However with a greater level of stenosis (0.16mm coil)
ischaemic damage to neuronal perikarya was present in most experimental animals.
In addition to ischaemic damage, localised areas of severe white matter pathology
were also observed in conjunction with subtle changes to white matter Ab levels.
Hypoperfusion did not impact on the development of intraneuronal Ab pathology,
other than in the presence of ischaemic damage when levels were reduced.
Comparison of CoW architecture between WT and 3xTg-AD mice revealed strain
specific differences in the presence and morphology of the posterior communicating
artery which may explain the lack of pathology in 3xTg-AD mice as compared to
WT following BCAS induced using 0.18mm dia. microcoils. The third aim was to investigate whether white matter protein composition
changed with age and also whether ageing conferred increased vulnerability to
hypoperfusion. To address this, white matter protein levels were compared between
young (3-4 months) and old (12-13 months) 3xTg-AD mice. White matter
pathology was compared between sham and hypoperfused animals in the aged
cohort. Levels of myelin basic protein and 2', 3'-cyclic nucleotide 3'-
phosphodiesterase were found to be significantly increased whilst levels of myelin
associated glycoprotein were significantly reduced with ageing. These results
suggest that changes in myelin protein composition may contribute to the
development of age related white matter pathology. White matter pathology was not
exacerbated in aged hypoperfused animals following one month of hypoperfusion as
compared to shams.
The results presented within the thesis demonstrate that chronic cerebral
hypoperfusion precipitates the development of selective white matter damage and
impacts on cognition. Also it has been shown that where hypoperfusion is severe
enough to cause ischaemic damage to neuronal perikarya and localised areas of
severe white matter pathology, alterations in white matter Ab levels can occur.
Hypoperfusion does not impact on APP processing or on intraneuronal levels of APP
or Ab, other than in the presence of ischaemic damage to neuronal perikarya, when
levels are reduced. These findings highlight the importance of early intervention
strategies in the treatment of vascular risk factors which can lead to hypoperfusion
and the development of white matter damage and a decline in cognitive function in
later life. These findings also suggest that repair or prevention of white matter
damage may be an appropriate strategy for the attenuation of cognitive decline following onset of hypoperfusion. This thesis also highlights some of the limitations
of animal models of human disease.